ABSTRACT Cutaneoussquamouscellcarcinoma(cSCC)isthesecondmostcommoncancerintheUnitedStates, affectingoveramillionpeopleannually,andwithsignificantmortalityduetometastasis.Despiteitprevalence andhightreatmentcosts,cSCCsarenotincludedinlarge-scalecancergenomicseffortsaimedat understandingthegeneticchangesarisingincancercells,suchasTheCancerGenomeAtlas(TCGA)project. Thus,genomicalterationsincSCChavenotbeencomprehensivelycharacterized,andnovel,molecularly- targetedtreatmentshavenotbeendeveloped.Thisproposal,modeledafterTCGAwhichisco-ledbyDr.Gad Getz(Co-Iofthisapplication),representsthelargesteffortofitskindtoanalyzegenomicchangesthatdrive cSCCprogression.Thiscriticaldataisneededtoidentifytargetsfornoveltreatmentandpreventionstrategies ofcSCC.Ourteamwasthefirsttopublishagenome-wideassociationstudythatidentifiedtennovelgermline lociassociatedwithincreasedcSCCriskusingthelargeGeneticEpidemiologyResearchonAging(GERA) cohort.Theoverallscientificobjectiveofthisproposalistoidentifyandintegratenoveltumor mutationaldatawithpreviouslycharacterizedinformationonhostgeneticriskfactorsandclinicalrisk factorstobetterunderstandhowcancerriskallelescontributetothedevelopmentofcSCCscapableof metastasis.Wewillanalyze290cSCCs(145primarycSCCsthatprogressedtometastasisand145non- metastaticprimarycSCCs)arisinginthewell-characterizedGERAcohorttoprovideacomprehensive landscapeofgenomicalterationsincSCCs.Weproposethefollowingspecificaims:1)characterizethe genomeandtransciptomeof290cSCCswithexistinggermlinedatausingatieredapproachincludingwhole- exome,whole-genome,andRNAsequencingtoidentifydrivermutations,aswellasepigenomicchanges;?2) integratethesomaticmutationalanalysiswithenvironmentalexposuredatatounderstandhowenvironmental exposuresimpactcSCCswithdistinctsomaticmutationalprofiles;?and3)developaclinicallymeaningfulrisk predictiontoolforidentifyingsubjectsatriskformetastaticcSCCsthatcombinesgermline,somatic,and clinicaldata.Theapproachisinnovativebecauseitwillincreaseunderstandingofthejointcontributionofthe germlineandsomaticgenomesforcSCCriskanditwillcreateapubliclyaccessiblecSCCgenomicdataportal providinganovelresourceforthescientificcommunity.Theproposedresearchissignificantbecauseitwill integrategermlineandsomaticgeneticdatatogainacomprehensivepictureofhowthegeneticsofboththe personandthetumorinteracttoaffectcSCCevolutionandprogression.Thecomprehensive,integrated characterizationofkeygenomicchangesinoneofthemostprevalentandcostlycancerswillsupport advancesindevelopingmoreeffectivewaystodiagnose,treatandpreventcSCCsandpotentiallysquamous cellcarcinomaarisinginotherorgans.